rs745319034

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_014270.5(SLC7A9):c.614dupA(p.Asn206GlufsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

SLC7A9
NM_014270.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.33

Publications

8 publications found

Variant links:

Genes affected

SLC7A9 (HGNC:11067): (solute carrier family 7 member 9) This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule. Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids. Alternate transcript variants, which encode the same protein, have been found for this gene. [provided by RefSeq, Jul 2011]

SLC7A9 Gene-Disease associations (from GenCC):

cystinuria
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
cystinuria type B
Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

SLC7A9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 19-32862207-C-CT is Pathogenic according to our data. Variant chr19-32862207-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 288197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014270.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC7A9	NM_014270.5	MANE Select	c.614dupA	p.Asn206GlufsTer3	frameshift	Exon 6 of 13	NP_055085.1
SLC7A9	NM_001126335.2		c.614dupA	p.Asn206GlufsTer3	frameshift	Exon 6 of 13	NP_001119807.1
SLC7A9	NM_001243036.2		c.614dupA	p.Asn206GlufsTer3	frameshift	Exon 6 of 13	NP_001229965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC7A9	ENST00000023064.9	TSL:1 MANE Select	c.614dupA	p.Asn206GlufsTer3	frameshift	Exon 6 of 13	ENSP00000023064.3
SLC7A9	ENST00000587772.1	TSL:1	c.614dupA	p.Asn206GlufsTer3	frameshift	Exon 6 of 13	ENSP00000468439.1
SLC7A9	ENST00000590341.5	TSL:1	c.614dupA	p.Asn206GlufsTer3	frameshift	Exon 6 of 13	ENSP00000464822.1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000147

AC:

AN:

251254

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000555

AC:

811

AN:

1461466

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

399

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33472

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000695

AC:

773

AN:

1111644

Other (OTH)

AF:

0.000381

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000170

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:8

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asn206GlufsX3 (NM_014270.4 c.614dupA) variant in SLC7A9 (also referred to as c.799insA or c.800?801insA in the literature) has been reported in at least 2 5 heterozygotes, 2 homozygotes, and 2 compound heterozygotes with cystinuria (Le clerc 2002, Font-Llitjos 2005, Barbosa 2012, Rhodes 2015, and Halbritter 2015). Twenty one heterozygotes were noted to have non-type I cystinuria (heterozygotes with moderate to high excretion of cystine in urine and risk of forming urinary tract stones) (Font-Llitjos 2005, Barbosa 2012, Halbritter 2015). This variant has also been reported in ClinVar (Variation ID#288197), as pathogenic by two la boratories. It has been identified in 0.024% (30/126,648) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs745319034). This variant is predicted to cause a frameshift, which alte rs the protein?s amino acid sequence beginning at position 206 and leads to a pr emature termination codon 3 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Loss of function of the SLC7A9 g ene is an established disease mechanism in cystinuria. Variants associated with non-type I cystinuria, such as this variant, are inherited in an autosomal domin ant manner with incomplete penetrance and cause more severe disease in the homoz ygous or compound heterozygous state. In summary, although additional studies a re required to fully establish its clinical significance, the p.Asn206GlufsX3 va riant is pathogenic for cystinuria in an autosomal dominant manner with incompl ete penetrance based on its occurrence in affected individuals and a predicted n ull effect.

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1,PS4_SUP,PM2_SUP

Nov 16, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC7A9 c.614dupA (p.Asn206GlufsTer3) variant, also referred to as c.799insA, has been reported in five studies in a total of 33 individuals with cystinuria, including three homozygotes, eight compound heterozygotes, and 22 heterozygotes with varying disease types (Leclerc et al. 2002; Font-Llitjos et al. 2005; Barbosa et al. 2012; Rhodes et al. 2015; Halbritter et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Asn206GlufsTer3 variant results in a frameshift, and is predicted to truncate the protein. While cystinuria generally displays an autosomal recessive mode of inheritance, some heterozygous carriers of variants in the SLC7A9 gene have abnormal urinary amino acid patterns and an increased risk of kidney stones (Eggermann et al. 2012). Based on the evidence and due to the potential impact of frameshift variants, the p.Asn206GlufsTer3 variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cystinuria (MIM#220100). (I) 0108 - This gene is associated with both recessive and dominant disease. Some heterozygous variants have been reported to present with a milder phenotype (OMIM, PMID: 11157794). (I) 0112 - The condition associated with this gene has incomplete penetrance. Autosomal dominant cystinuria has been reported to have incomplete penetrance (PMID: 25964309). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 41 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories (ClinVar), and has been observed as heterozygous, compound heterozygous and homozygous variants in multiple unrelated individuals with cystinuria (PMID: 12379955; 25964309; 28646536) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Oct 03, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG:PVS1, PM2, PM3, PP5

not provided

Pathogenic:4

Jun 01, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 09, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple unrelated patients from different ethnic backgrounds with type II and type III cystinuria or with cystinuria and nephrolithiasis in published literature (PMID: 25296721, 12371955); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12371955, 26990548, 25296721, 30609409, 29431110, 37279760, 28717662)

Oct 16, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asn206Glufs*3) in the SLC7A9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC7A9 are known to be pathogenic (PMID: 11157794, 16838140, 25296721). This variant is present in population databases (rs745319034, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cystinuria in the heterozygous state (PMID: 12371955, 15635077, 16834950, 19782624, 21255007, 25109415, 25296721, 25964309). It has also been observed to segregate with disease in related individuals. This variant is also known as 799insA and c.800-801insA. ClinVar contains an entry for this variant (Variation ID: 288197). For these reasons, this variant has been classified as Pathogenic.

SLC7A9-related disorder

Pathogenic:1

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLC7A9 c.614dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn206Glufs*3). This common pathogenic SLC7A9 variant in the heterozygous state has been reported to cause moderate or severe cystinuria in different families, suggesting an autosomal dominant mode of inheritance (reported as 799insA at Leclerc et al. 2002. PubMed ID: 12371955). This variant has also been reported in the homozygous or compound heterozygous state in many unrelated individuals to cause cystinuria (Rhodes et al. 2015. PubMed ID: 25964309; Bisceglia et al. 2010. PubMed ID: 19782624; Barbosa et al. 2011. PubMed ID: 21255007). In summary, the c.614dup is classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over